The 2C-methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of
isopentenyl pyrophosphate and its isomer dimethylallyl
pyrophosphate, which are the precursors of
isoprenoids, is present in plants, in the
malaria parasite Plasmodium falciparum and in most eubacteria, including pathogenic agents. However, the MEP pathway is absent from fungi and animals, which have exclusively the
mevalonic acid pathway. Given the characteristics of the MEP pathway, its
enzymes represent potential targets for the generation of selective antibacterial,
antimalarial and herbicidal molecules. We have focussed on the
enzyme 4-(cytidine 5'-diphospho)-2-C-methyl-D-erythritol
kinase (CMK), which catalyses the fourth reaction step of the MEP pathway. A molecular dynamics simulation was carried out on the CMK dimer complex, and
protein-
protein interactions analysed, considering also water-mediated interactions between monomers. In order to find small molecules that bind to CMK and disrupt dimer formation, interactions observed in the dynamics trajectory were used to model a pharmacophore used in database searches. Using an intensity-fading matrix-assisted
laser desorption/ionisation time-of-flight mass spectrometry approach, one compound was found to interact with CMK. The data presented here indicate that a virtual screening approach can be used to identify candidate molecules that disrupt the CMK-CMK complex. This strategy can contribute to speeding up the discovery of new
antimalarial, antibacterial, and herbicidal compounds.